Overexpression of human lecithin:cholesterol acyltransferase in mice offers no protection against diet-induced atherosclerosis

Human lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the metabolism of cholesterol. We have used homozygous transgenic mice overexpressing the human LCAT transgene to study the effect of a "Western-type" atherogenic diet (30% fat, 5% cholesterol and 2% cholic acid) on their LCAT expression, activity, lipoprotein profile and tendency to develop atherosclerosis. The LCAT activity was 35-fold higher in serum of the homozygous transgenic mice than in murine control serum, and decreased 11-20% in the transgenic mice when fed the atherogenic diet. The total cholesterol and high-density lipoprotein cholesterol (HDL-C) concentrations were approximately doubled in the transgenic mice compared with the controls when both groups were fed a regular chow diet. In mice on the atherogenic diet, the triglyceride concentration decreased about 50% to the same level in transgenic and control mice. Total cholesterol and HDL-C concentrations increased and were 60-80% higher in the transgenic mice. The expression of LCAT mRNA in the liver was decreased by 49-60% in the transgenic mice when fed the atherogenic diet. The development of atherosclerosis was similar in transgenic and control mice. Thus, the 14- to 27-fold higher LCAT activity and the higher HDL-C concentrations in the homozygous LCAT transgenic mice had no significant protective influence on the development of diet-induced atherosclerosis.     

Angiochemical and tissue cholesterol changes of Macaca fascicularis fed an atherogenic diet for 3 years.

Angiochemical and tissue cholesterol changes were investigated in Macaca fascicularis fed either an atherogenic containing 1 mg cholesterol/Cal or a control diet for 3 years. The thoracic and abdominal aortas and the carotid and femoral arteries were visually examined for the extensiveness of atherosclerosis and analyzed for lipid, collagen, elastin, and mineral content. Cholesterol accumulation in other tissues was assessed by measuring concentrations in liver, kidney, skin, and tendon. The cynomolgus macaques fed the atherogenic diet had between 77 and 97% of the intimal surface of all arteries studied affected with atherosclerotic lesions. The arteries of animals fed the atherogenic diet were between 1.6–2.5 times heavier than the arteries of control animals. This increased weight was attributed largely to collagen and elastin. When animals fed the atherogenic diet were compared with controls, significant increases in arterial total cholesterol, esterified cholesterol, phospholipid, calcium, phosphorus, and magnesium were seen. The liver, skin and tendon, but not the kidney, had significant increased concentrations of total and esterified cholesterol compared to control tissues. Comparison of our findings with the results of other studies of nonhuman primates indicates that the atherosclerotic plaques induced in the cynomolgus macaques are most nearly comparable to atherosclerosis in man, primarily because of the marked accumulation of mineral and connective tissue components.     

Hyperlipoproteinaemia and atherosclerosis in rabbits fed low-level cholesterol and lecithin

Dutch-Belted rabbits were fed for 18 months an atherogenic semipurified gel diet containing 14% hydrogenated coconut oil and 0.06% cholesterol (approximately 0.15 mg/kcal) or a non-atherogenic basal gel diet containing the same ingredients but with no coconut oil or cholesterol. Rabbits fed atherogenic diet developed hypercholesterolaemia (means 733 mg/dl at 16 months) and plasma lipoprotein (LP) distribution shifted from a pattern in which high-density lipoproteins (HDL) predominated to one in which very-low-density lipoproteins (VLDL) were predominant. Total cholesterol/triglyceride ratio in d less than 1.006 LP changed from 0.3 to 1.8. Plasma cholesterol and LP distribution returned to normal in rabbits fed atherogenic diet for 18 months followed by atherogenic diet plus 3% soya lecithin for an additional 4 months. Rabbits fed atherogenic diet for 18 months had extensive, usually full circumference fibromuscular plaques in main branches of coronary arteries and all portions of aorta which compromised lumen area by almost 50%. These lesions were modified in rabbits fed atherogenic diet plus lecithin. The plaques lacked foam cells and cholesterol clefts, were less cellular with a distinct fibrous surface and occupied less space. Animals fed basal diet did not develop hypercholesterolaemia (means 86 mg/dl at 16 months), although distribution of plasma LP shifted slightly in favour of increased low-density lipoproteins (LDL) and decreased HDL compared with rabbits fed standard commercial diet. Basal diet rabbits had no coronary atherosclerosis and only minimal focal foam cell lesions in proximal aorta. Liver injury including fatty change, cholangitis and portal fibrosis occurred in animals fed atherogenic diet. Thus, rabbits fed appropriate diets low in cholesterol accumulate cholesterol-enriched LP in their plasma and develop lesions in abdominal aorta and main branches of coronary arteries which are similar to those in man. Also, in this experimental model, dietary lecithin promotes a return to normal of the LP distribution profile and removal of lipid from established atherosclerotic plaque.     

Hyperlipoproteinaemia and atherosclerosis in rabbits fed low-level cholesterol and lecithin.

Dutch-Belted rabbits were fed for 18 months an atherogenic semipurified gel diet containing 14% hydrogenated coconut oil and 0.06% cholesterol (approximately 0.15 mg/kcal) or a non-atherogenic basal gel diet containing the same ingredients but with no coconut oil or cholesterol. Rabbits fed atherogenic diet developed hypercholesterolaemia (means 733 mg/dl at 16 months) and plasma lipoprotein (LP) distribution shifted from a pattern in which high-density lipoproteins (HDL) predominated to one in which very-low-density lipoproteins (VLDL) were predominant. Total cholesterol/triglyceride ratio in d less than 1.006 LP changed from 0.3 to 1.8. Plasma cholesterol and LP distribution returned to normal in rabbits fed atherogenic diet for 18 months followed by atherogenic diet plus 3% soya lecithin for an additional 4 months. Rabbits fed atherogenic diet for 18 months had extensive, usually full circumference fibromuscular plaques in main branches of coronary arteries and all portions of aorta which compromised lumen area by almost 50%. These lesions were modified in rabbits fed atherogenic diet plus lecithin. The plaques lacked foam cells and cholesterol clefts, were less cellular with a distinct fibrous surface and occupied less space. Animals fed basal diet did not develop hypercholesterolaemia (means 86 mg/dl at 16 months), although distribution of plasma LP shifted slightly in favour of increased low-density lipoproteins (LDL) and decreased HDL compared with rabbits fed standard commercial diet. Basal diet rabbits had no coronary atherosclerosis and only minimal focal foam cell lesions in proximal aorta. Liver injury including fatty change, cholangitis and portal fibrosis occurred in animals fed atherogenic diet. Thus, rabbits fed appropriate diets low in cholesterol accumulate cholesterol-enriched LP in their plasma and develop lesions in abdominal aorta and main branches of coronary arteries which are similar to those in man. Also, in this experimental model, dietary lecithin promotes a return to normal of the LP distribution profile and removal of lipid from established atherosclerotic plaque.     

Experimental atherosclerosis in swine: effect of dietary protein and high fat

Two groups of pigs each consisting of 6 animals were fed for 18 months on isocaloric amounts of an experimental diet with a high fat content and cholesterol but with widely different levels of protein (5% vs. 25% by weight of the diet). In addition, a third group consisting of 4 animals was maintained on normal stock diet to serve as control.Animals of the low protein group showed the maximal intimal surface area involvement with atherosclerotic lesions in the aorta and coronary arteries, and also the most severe among the three groups. No significant differences were noted in the extent and severity of lesions between the high protein-high fat fed animals as compared with the high protein-low fat fed controls. Lesions of the low protein group had a higher cholesterol content and a raised cholesterol:phospholipid ratio than those in the other two groups.Extremely low levels of dietary proteins seem to have had a promotive effect on the induction of atherosclerotic lesions by an atherogenic diet, whereas adequate levels of dietary proteins have had a protective influence. The precise mechanism by which varying levels of dietary proteins have such effects is not understood. It may possibly be related to the aberrations of lipid metabolism induced by extremely low levels of dietary proteins.     

MaxEPA fish oil enhances cholesterol-induced intimal foam cell formation in rabbits.

In this study, the cholesterol-fed rabbit model was used to test the hypothesis that fish oil supplementation can influence the initiation and development of atherosclerotic lesions. Rabbits were fed one of two diets for a period of 30 days: a nonatherogenic diet with corn oil as the sole fat source, or an atherogenic diet containing beef tallow and cholesterol. In addition, animals received a daily supplement of either MaxEPA fish oil or corn oil (0.5 ml/kg body weight). Terminal blood samples were drawn and the cholesterol and triglyceride levels determined for both plasma and very low-density (VLDL), intermediate-density (IDL), low-density (LDL), and high-density (HDL) lipoproteins. Thiobarbituric acid-reacting substance (TBARS), an indicator of lipid peroxidation, was measured in the plasma samples. Besides these biochemical parameters of atherogenesis, the number of intimal foam cells in the descending thoracic aorta of each animal was determined by microscopic examination of the vessels en face. In rabbits fed the nonatherogenic diet, fish oil supplementation did not significantly affect any of the biochemical parameters that were measured. In contrast, fish oil supplementation of the atherogenic diet led to a significant increase in the LDL- and HDL-cholesterol as well as the HDL-triglyceride levels. Plasma TBARS also increased more than four times. Morphologic analysis of the vessels from rabbits fed the atherogenic diet indicated that fish oil supplementation led to a threefold increase in the number of intimal foam cells, a result that may be linked to increases in both LDL-cholesterol and plasma TBARS. The results of these experiments do not support the hypothesis that dietary fish oil will inhibit the initiation or progression of lesion formation in the cholesterol-fed rabbit.     

Comparative primate atherosclerosis: I. Tissue Cholesterol Concentration and Pathologic Anatomy

Stump-tailed macaques (Macaca arctoides), African green monkeys (Cercopithecus aethiops), squirrel monkeys (Saimiri sciureus), and woolly monkeys (Lagothrix lagothricha) were fed control, solid atherogenic (1 mg cholesterol/cal) or liquid diets containing 0, 0.5, or 1 mg cholesterol/cal.Stump-tailed macaques fed the solid atherogenic diet had the highest tissue and serum cholesterol concentration (about 700 mg/dl) and the most extensive atherosclerosis. These monkeys appeared to respond differently to diets containing 1 mg cholesterol/cal. Those animals fed the liquid diet had higher liver cholesterol concentration but lower serum cholesterol concentration than animals fed the solid diet. African green monkeys fed the solid atherogenic diet had serum cholesterol concentrations of about 450 mg/dl. A greater percentage of the abdominal aorta was covered by plaque than the thoracic aorta. Coronary artery atherosclerosis was focal with the largest plaques being found in the left main coronary artery. The microscopic appearance of these plaques was similar to that of plaques from people.Squirrel monkeys fed the atherogenic diet were the most variable group. The average serum cholesterol concentration averaged about 450 mg/dl (range: 291 to 716). The percentage of aorta covered by plaque ranged from 0 to 55% with more thoracic than abdominal aortic atherosclerosis. There were findings consistent with hemorrhage in plaques from two animals. These monkeys, like stump-tailed macaques but unlike African green monkeys had relatively high liver cholesterol concentrations.Woolly monkeys appeared to develop atherosclerosis when fed 1 mg cholesterol/cal but did not have greatly elevated serum cholesterol concentrations.     

Antioxidant and anti-atherogenic activities of three Piper species on atherogenic diet fed hamsters

Atherogenic diet is known to induce high plasma lipid concentration, oxidative stress and early atherosclerosis. Antioxidants have potentials to counter the effect of atherogenic diet.The present research aims at evaluating the antioxidant and anti-atherosclerotic activities of three Piper species (Piper guineense, Piper nigrum and Piper umbellatum) on atherogenic diet fed hamsters.Hamsters divided into 8 groups: normal control, atherosclerotic control and six test groups. The normal animals fed normal rodent chow, the atherosclerotic control animals fed the same rodent chow supplemented with 0.2% cholesterol and 10% coconut oil (high cholesterol diet). The 6 test groups’ animals fed same diet as the atherosclerotic control group but with additional supplementation of 2 graded doses (1 and 0.25 mg/kg body weight, o.p.) of plant extracts for 12 weeks.The atherogenic diet induced a collapse of the erythrocyte antioxidant defense system (significant decrease in superoxide dismutase, catalase and glutathione peroxidase activities). Atherogenic diet also induced an increase in plasma total cholesterol, triglyceride, thiobarbituric acid reactive substances (TBARS), oxidation of low density lipoprotein cholesterol (LDL) and accumulation of foam cells in the aorta a hall mark for atherosclerosis. Administration of the Piper species prevented the collapse of the antioxidant system and the increase of plasma parameters maintaining them towards normality. The Piper species also prevented LDL oxidation by increasing the time (lag time) for its oxidation.The results suggest that these Piper species have significant antioxidant and anti-atherogenic effect against atherogenic diet intoxication.     

Regression of Early Cholesterol-Induced Aortic Lesions in Rhesus Monkeys

The reversibility of early uncomplicated cholesterol-induced aortic lesions in rhesus monkeys was investigated. Three groups of Rhesus monkeys were used: the control group was fed a chow diet for 8 weeks; the progression group was fed an atherogenic diet for 8 weeks and the regression group was fed an atherogenic diet for 8 weeks and returned to the chow diet for 16 weeks. The lesions produced in the progression animals characteristically contained many lipid-laden monocytes immediately beneath the endothelium, abundant lipid droplets in intimal smooth muscle cells and moderate amounts of lipid in the extracellular spaces. Lesions in regression animals contained few lipid-laden monocytes, less lipid in smooth muscle cells and larger and more numerous lipid particles in the extracellular spaces. The results indicate that aortic lesions can be produced predictably after 8 weeks of feeding a high-cholesterol diet and that qualitative changes in the lesions occur 16 weeks after withdrawal from the diet.     

Diet induced atherogenic hyperlipoproteinaemia and liver injury in cynomolgus macaques

This study was conducted to determine the efficacy of an experimental anti-atherosclerosis drug in the adult male cynomolgus monkey. A semipurified diet containing 0.5% cholesterol and 25.5% butter was fed to groups of 20, each, drug and placebo-treated animals for 18 months. Similar liver and arterial changes were present in both groups. However, we report here tissue changes seen in animals given placebo only, with plasma lipid and lipoprotein values of placebo-treated animals compared to those in animals fed nonatherogenic commercial ration. Animals fed atherogenic diet had enlarged livers (mean 3.9% b.w.), and all had evidence of hepatocellular lipid accumulation which was often marked and diffuse. Cholangitis was common including mononuclear cell infiltration, bile ductule proliferation and portal tract fibrosis. Five animals had severe portal fibrosis with bands of connective tissue extending into and around lobules (bridging fibrosis). All animals fed atherogenic diet developed hypercholesterolemia (greater than 600 mg/dl) which was the result of a three-fold increase in five cholesterol and cholesterol ester. Oleic acid was increased and linoleic acid was reduced in plasma phospholipids and cholesterol esters. Plasma lipoprotein distribution was altered with a marked increase in low density lipoproteins, increased very low density lipoproteins and decreased high density lipoproteins. These changes were undoubtedly caused by diet, i.e., high in cholesterol and saturated fat and limiting in linoleic acid. It is probable that diet-induced liver injury would affect the pathogenesis of atherosclerosis in this model since the liver is central in the synthesis and metabolism of lipoproteins.     

Diet induced atherogenic hyperlipoproteinaemia and liver injury in cynomolgus macaques.

This study was conducted to determine the efficacy of an experimental anti-atherosclerosis drug in the adult male cynomolgus monkey. A semipurified diet containing 0.5% cholesterol and 25.5% butter was fed to groups of 20, each, drug and placebo-treated animals for 18 months. Similar liver and arterial changes were present in both groups. However, we report here tissue changes seen in animals given placebo only, with plasma lipid and lipoprotein values of placebo-treated animals compared to those in animals fed nonatherogenic commercial ration. Animals fed atherogenic diet had enlarged livers (mean 3.9% b.w.), and all had evidence of hepatocellular lipid accumulation which was often marked and diffuse. Cholangitis was common including mononuclear cell infiltration, bile ductule proliferation and portal tract fibrosis. Five animals had severe portal fibrosis with bands of connective tissue extending into and around lobules (bridging fibrosis). All animals fed atherogenic diet developed hypercholesterolemia (greater than 600 mg/dl) which was the result of a three-fold increase in five cholesterol and cholesterol ester. Oleic acid was increased and linoleic acid was reduced in plasma phospholipids and cholesterol esters. Plasma lipoprotein distribution was altered with a marked increase in low density lipoproteins, increased very low density lipoproteins and decreased high density lipoproteins. These changes were undoubtedly caused by diet, i.e., high in cholesterol and saturated fat and limiting in linoleic acid. It is probable that diet-induced liver injury would affect the pathogenesis of atherosclerosis in this model since the liver is central in the synthesis and metabolism of lipoproteins.     

Dietary induced hyperbetalipoproteinemia in chimpanzees: comparison to the human hyperlipoproteinemia

Fasting plasma from chimpanzees fed normal and atherogenic diet was separated into alpha (HDL) and beta (LDL) lipoproteins by electrochromatography. Both lipoproteins were analyzed for lipid and fatty acid composition.Beta lipoproteins, esterified cholesterol, free cholesterol, and phospholipids were increased in chimpanzees fed the atherogenic diet. The cholesterol/phospholipid ratio was increased. These lipid changes occurred chiefly in the beta lipoproteins. A disproportionate increase of plasma phosphatidylcholine to sphingomyelin was confirmed. Differences in the fatty acid composition of both lipoproteins were noted and cholesterol oleate was elevated more than cholesterol linoleate so that the $\text{18:1}\text{18:2}$ ratio was increased. The intima of one animal which died from myocardial infarction after 4–5 years diet showed an increase of cholesterol oleate.Similarities between cholesterol-induced lipoprotein changes in chimpanzees and those obtained in human hyperbetalipoproteinemia are discussed. These similarities stress the usefulness of these nonhuman primates as a model for experimental atherosclerosis and for studying the molecular changes in lipoprotein patterns.     

Effects of chlorella phospholipid on the aortic collagen and elastin metabolism and on the serum lipid content in rats with experimental arteriosclerosis

Rats treated with 44,800 IU of vitamin D₂ for 4 consecutive days were fed an atherogenic diet in the presence or absence of 1% chlorella phospholipid. Control rats received a basal diet and were administered olive oil. After 2 months the animals were killed and aortic prolyl hydroxylase, lysyl oxidase activity, collagen, elastin, and serum lipid levels were determined. Aortic prolyl hydroxylase activity was significantly decreased in rats receiving the atherogenic diet in the absence of chlorella phospholipid. The aortic collagen and elastin content was lower in rats additionally treated with chlorella phospholipid. Aortic lysyl oxidase activity was significantly decreased in all rats receiving the atherogenic diet. The serum cholesterol level was significantly higher in rats on the atherogenic diet, especially the absence of chlorella phospholipid supplementation. The findings suggest that the administration of chlorella phospholipid may stimulate the degradation of collagen and elastin in the aorta of rats fed an atherogenic diet and that the serum cholesterol lowering effect of chlorella phospholipid is not ascribable to thyroid functions. Furthermore, the results suggest that the aortic degradation rate of elastin was reduced by the atherogenic treatment.     

Effects of diltiazem on suppression and regression of experimental atherosclerosis.

The effects of diltiazem (a calcium antagonist) on the suppression and regression of atherosclerosis were studied. Thirty-one rabbits were fed a 1% cholesterol (atherogenic) diet together with saline (n = 22) or diltiazem (n = 9) injections. After 10 weeks, seven rabbits that received saline and nine rabbits that received diltiazem were killed. The remaining 15 saline-treated rabbits were then put on a standard (regression) diet for the next 15 weeks with saline (n = 7) or diltiazem (n = 8) injections. Sixteen rabbits given a standard diet were used as controls. At 5 and 10 weeks, the plasma LDL cholesterol level in rabbits on the atherogenic diet with diltiazem was significantly lower than in those on the atherogenic diet with saline. The aortic total cholesterol, esterified cholesterol and calcium contents were also significantly lower in rabbits on the atherogenic diet with diltiazem. After 25 weeks (15 weeks on the regression diet), the differences in aortic total cholesterol and calcium contents between the two groups on the regression diet were not significant; however, the aortic esterified cholesterol content was significantly lower in the regression diet with diltiazem. The results suggest that diltiazem has a favourable effect both on regression and on suppression of atherosclerosis.     

Effects of diltiazem on suppression and regression of experimental atherosclerosis

The effects of diltiazem (a calcium antagonist) on the suppression and regression of atherosclerosis were studied. Thirty-one rabbits were fed a 1% cholesterol (atherogenic) diet together with saline (n = 22) or diltiazem (n = 9) injections. After 10 weeks, seven rabbits that received saline and nine rabbits that received diltiazem were killed. The remaining 15 saline-treated rabbits were then put on a standard (regression) diet for the next 15 weeks with saline (n = 7) or diltiazem (n = 8) injections. Sixteen rabbits given a standard diet were used as controls. At 5 and 10 weeks, the plasma LDL cholesterol level in rabbits on the atherogenic diet with diltiazem was significantly lower than in those on the atherogenic diet with saline. The aortic total cholesterol, esterified cholesterol and calcium contents were also significantly lower in rabbits on the atherogenic diet with diltiazem. After 25 weeks (15 weeks on the regression diet), the differences in aortic total cholesterol and calcium contents between the two groups on the regression diet were not significant; however, the aortic esterified cholesterol content was significantly lower in the regression diet with diltiazem. The results suggest that diltiazem has a favourable effect both on regression and on suppression of atherosclerosis.     

Functional alteration of endothelium by short-term cholesterol feeding

The influence of varying periods of cholesterol feeding and of superimposed endothelial denudation on the transmural transport of albumin has been studied in rabbit carotid artery perfused in vivo with Dulbecco's modified Eagle's medium. The concentration of labeled albumin in jugular venous blood was measured serially over 4 hr and was used as the index of arterial transport. Three groups of rabbits were fed a diet containing 1.5% cholesterol for either 1, 3-7, or 12-28 weeks. A significant increase in albumin transport across the carotid artery was noted in all groups when compared to control animals who were fed a standard rabbit chow. The transport abnormalities observed after 1 week occurred in the absence of any grossly visible atherosclerotic lesions or of any evidence of endothelial cell loss by scanning electron microscopy. In an additional group of rabbits who were fed the cholesterol diet for 16-28 weeks and in which endothelial denudation was performed just prior to carotid perfusion, removal of carotid artery endothelium did not cause a further enhancement of albumin transport above that observed by cholesterol feeding alone. The findings suggest that cholesterol feeding of even very brief duration can alter endothelial function and enhance arterial permeability to albumin.     

Ultrastructural studies of the mouse aorta and its endothelial pinocytosis in diet-induced arteriosclerosis

In mice fed on an atherogenic diet for 4 to 8 months, the aortas were examined by transmission and scanning electron microscopy. After 8 months of being fed a high cholesterol diet, the animals developed aortic intimal lesions composed mainly of proliferated modified smooth muscle cells with an increase of connective tissues. Scanning electron microscopy showed changes in aortic luminal surface consisting primarily of altered distribution of microvilli. Quantitative analysis of these changes showed a statistically significant (P less than 0.001) increase in cholesterol-fed animals compared with controls and a significant (P less than 0.001) difference between at 4 months and at 8 months in cholesterol-fed mice. Ultrastructural study on the uptake of protein tracer, horseradish peroxidase (HRP), by aortic endothelial cells in vitro was performed. The uptake of HRP was essentially the same for controls and cholesterol-fed mice at 4 months, but a statistically significant (P less than 0.005) increased uptake of HRP was observed at 8 months. Additional mice were subjected to nephrectomy with DOCA administration for 4 months along with a cholesterol-feeding. These animals showed a 2-fold increase in HRP-uptake compared with nephrectomized mice without a cholesterol-feeding. These results suggest that the enhanced pinocytotic activity of aortic endothelial cells in vitro, especially in hypertensive condition, and altered distribution of microvilli might be correlated to the arteriosclerotic process.     

ULTRASTRUCTURAL STUDIES OF THE MOUSE AORTA AND ITS ENDOTHELIAL PINOCYTOSIS IN DIETINDUCED ARTERIOSCLEROSIS

In mice fed on an atherogenic diet for 4 to 8 months, the aortas were examined by transmission and scanning electron microscopy. After 8 months of being fed a high cholesterol diet, the animals developed aortic intimal lesions composed mainly of proliferated modified smooth muscle cells with an increase of connective tissues. Scanning electron microscopy showed changes in aortic luminal surface consisting primarily of altered distribition of microvilli. Quantitative analysis of these changes showed a statistically significant (P<0.001) increase in cholesterol-fed animals compared with controls and a significant (P<0.001) difference between at 4 months and at 8 months in cholesterol-fed mice. Ultrastructural study on the uptake of protein tracer, horseradish peroxidase (HRP), by aortic endothelial cells in vitro was performed. The uptake of HRP was essentially the same for controls and cholesterol-fed mice at 4 months, but a statistically significant (P<0.005) increased uptake of HRP was observed at 8 months. Additional mice were subjected to nephrectomy with DOCA administration for 4 months along with a cholesterol-feeding. These animals showed a 2-fold increase in HRP-uptake compared with nephrectomized mice without a cholesterol-feeding. These results suggest that the enhanced pinocytotic activity of aortic endothelial cells in vitro , especially in hypertensive condition, and altered distribution of microvilli might be correlated to the arteriosclerotic process.     

Aortic total glycosaminoglycan and dermatan sulfate changes in atherosclerotic rhesus monkeys.

The composition and content of aortic glycosaminoglycans were studied in groups of rhesus monkeys fed control or atherogenic diets for 9 or 19 months. Aortic uronic acid content was significantly increased in both groups of monkeys with atherosclerosis. The major glycosaminoglycan in both control and atherosclerotic aortas was chondroitin sulfate with lesser amounts of heparan sulfate, dermatan sulfate, and hyaluronic acid. Dermatan sulfate was the only glycosaminoglycan to show a statistically significant elevation (65 to 87 per cent) in animals fed the atherogenic diet. This increase was positively correlated with the increased accumulation of aortic cholesterol (r = 0.4709, p less than 0.05). The results indicate that dermatan sulfate may be the major glycosaminoglycan involved during the early events of atherogenesis perhaps through retention of lipoprotein in the atherosclerotic artery.     

Myocardial infarction in a large colony of nonhuman primates with coronary artery atherosclerosis.

Relatively few cases of myocardial infarction associated with coronary artery atherosclerosis have been described previously in macaques. In this study the authors report the prevalence and characteristics of coronary artery atherosclerosis and myocardial infarction in 10 rhesus (Macaca mulatta) and two cynomolgus (Macaca fascicularis) macaques that were fed atherogenic diets for 16 months or longer. Our findings show clearly that myocardial infarction occurs in macaques with diet-induced atherosclerosis. The frequency seems to be related to the species, composition of the atherogenic diet, and length of time fed the atherogenic diet. The myocardial lesions are remarkably similar to those described in human beings in terms of location and gross and microscopic characteristics. The characteristics of coronary artery atherosclerosis, including the occurrence of thrombosis, severe stenosis, mineralization, atheronecrosis, and sterol clefts, especially in animals fed the atherogenic diets for longer periods of time, also closely resemble those of the arterial lesions found in human beings. The greatest prevalence of myocardial infarcts was found in rhesus monkeys fed a cholesterol-containing diet with 40% of calories supplied by peanut oil and in cynomolgus macaques from Malaya that were fed the same amount of cholesterol with 40% of calories from lard. Electrocardiographic abnormalities as well as the occurrence of unexpected and relatively sudden death in several of these nonhuman primates are also consistent with signs frequently observed in human beings.